The serine kinases IKK2 and JNK1 contribute to insulin resistance by phosphorylation of IRS-1. This activity has been widely used to explain insulin resistance for many risk factors including inflammation, lipotoxicity, ER stress and oxidative stress. Our study in the last funding period suggests that S6K and HDACs are targeted by the two serine kinases in the regulation of glucose and lipid metabolism. Our data suggests that IKK2 and JNK1 signals may be integrated in the S6K1 activation in the cytoplasm for IRS-1 inhibition. Their signals may also be combined in the regulation of PPARg activity in the nucleus through HDACs. Based on these observations, we hypothesize that S6K1 and HDACs may mediate signals of IKK2 and JNK1 in the regulation of glucose and lipid metabolism. However, the hypothesis remains to be tested and the details remain to be uncovered. We will address these issues in two specific aims: AIM I: To test that the IKK2-JNK1 signal integration may lead to S6K activation in the cytoplasm; AIM II: To test that the IKK2-JNK1 signal integration may control HDACs function in the nucleus. The results will provide a novel and unified mechanism for IKK2 and JNK1 in the regulation of glucose and fatty acid metabolism. The study may lead to identification of new drug target in prevention and treatment of metabolic syndrome. PUBLIC HEALTH RELEVANCE: Type 2 diabetes has been a major health threat to the general public in US. The treatment and prevention of the disease is limited by our understanding of the molecular mechanism of the diseases. In this study, we will investigate the molecular mechanism by focusing on two molecules IKK2 and JNK1. The study will help us to understand the molecular mechanisms, and to identify new drug target for type 2 diabetes.